PROJECT SUMMARY Computed tomography is used in about 80 million imaging studies per year in the USA. Iodinated contrast agents are used in roughly half of these studies. Computed tomography is particularly important for the diagnosis of coronary artery disease, where it depends on the use of iodinated contrast agents to visualize the arteries. However, these agents have a number of shortcomings, such as short circulation times, causing allergic reactions and contrast-induced nephropathy. The latter condition results in higher morbidity, mortality and costs and is most common in patients with poor kidney function. The proportion of patients over 65 with kidney disease is 26%. This percentage is rapidly rising, since the incidence of diabetes is rapidly increasing (projected to affect 30% of the US population by 2050) and kidney disease is a common complication of diabetes. The risk of cardiovascular disease is trebled for diabetics. Therefore there is a growing population that will suffer cardiovascular disease, but for whom the current diagnostic agents can be harmful, creating a pressing need for new CT contrast agents. Others and we have shown gold nanoparticles to be highly effective, biocompatible CT contrast agents that have long circulation times. However, gold nanoparticles are typically very slowly excreted, leading to the risk of long term toxicities and would preclude FDA-approval. Penn faculty, together with PolyAurum LLC, propose to address this issue via development of biodegradable gold nanoparticles. We have chosen a comparatively simple, yet flexible nanoparticle design in order to improve the likelihood of translation. The nanoparticles should circulate in the blood for some hours, before gradually breaking down into their components for renal excretion. Rapid excretion should be avoided to prevent a burden on the kidneys, but excretion should be reasonably fast to avoid the potential for long-term safety issues and confounding follow-up imaging studies. We will therefore study how to tune degradation to occur over 48 hours. We will confirm the biocompatibility of the new formulations in vitro. We will then ensure that the new formulation provides excellent in vivo CT contrast, as well as determining in vivo biocompatibility and excretion. After these experiments, we will be well placed to raise additional funds to complete toxicology screening to allow us to apply for investigational new drug (IND) status. Approval of the IND application would set the stage for clinical trials of the formulation.